Project Summary/Abstract The disease course of systemic onset juvenile idiopathic arthritis (sJIA) follows a peculiar pattern compared to other forms of inflammatory arthritis observed in children. The initial phase of the disease is heralded by high fevers, rash, and systemic inflammation, and only a subset of patients develops chronic arthritis. It is well known that IL-1? and IL-6 are key mediators of the systemic symptoms in early sJIA. Our ultimate goals are to better understand the factors that predispose some children to develop chronic arthritis in sJIA so that we can identify effective treatments and strategies to prevent arthritis in this condition altogether. This proposal outlines a research and training plan with a focus on regulatory T cell dysfunction as a mediator of arthritis in sJIA. The investigator conducted preliminary studies that showed abnormalities in Treg cells from patients with acute sJIA, including markedly increased IL-17 production and decreased frequencies of peripherally-induced Treg cells. Based on these findings and the known permissive effects IL-1? and IL-6 have on Th17 polarization, we hypothesize that the inflammatory cytokine environment in early sJIA transforms Treg cells into Th17-like-effector cells and blocks peripherally-induced Treg differentiation. The result is a Th17/Treg imbalance then drives chronic arthritis in sJIA. The proposed Specific Aims will test this hypothesis with human biosamples. In Aim 1, Treg stability and phenotype in sJIA will be determined through the use of mass cytometry, transcriptomics, and DNA methylations studies. Aim 2 evaluates the effects of IL-1? and IL-6 on Treg suppressive capacity and peripherally-induced Treg generation from nave CD4+ T cells. Using multidimensional immunoprofiling made possible by innovative technologies and functional assays, this project will allow the candidate to develop important skills that will provide the foundation for an independent research career. In the short term, the candidate?s goals are to develop a deeper understanding of Treg- mediated tolerance, leverage cutting-edge techniques such as mass cytometry and RNA sequencing to study patient samples, and master bioinformatic approaches to analyze large data sets. A team of mentors, advisors, and collaborators with the requisite expertise has been assembled to ensure success and allow the applicant to meet the ultimate objective of independence as a translational investigator in the field of pediatric rheumatology.